Proteins, carbohydrates and other biological molecules (“biological macromolecules”) are finding increasing use in many diverse areas of science and technology. For example, proteins are employed as active agents in the fields of pharmaceuticals, vaccines and veterinary products. Unfortunately, the use of biological macromolecules as active agents in pharmaceutical compositions is often severely limited by the presence of natural barriers of passage to the location where the active agent is required. Such barriers include the skin, lipid bi-layers, mucosal membranes, severe pH conditions and digestive enzymes.
Oral delivery of active agents is a particularly desirable route of administration, because of safety and convenience considerations and because oral delivery replicates the physiologic mode of insulin delivery. In addition, oral delivery provides for more accurate dosing than multidose vials and can minimize or eliminate the discomfort that often attends repeated hypodermic injections.
There are many obstacles to successful oral delivery of biological macromolecules. For example, biological macromolecules are large and are amphipathic in nature. More importantly, the active conformation of many biological macromolecules may be sensitive to a variety of environmental factors, such as temperature, oxidizing agents, pH, freezing, shaking and shear stress. In planning oral delivery systems comprising biological macromolecules as an active agent for drug development, these complex structural and stability factors must be considered.
In addition, in general, for medical and therapeutic applications, where a biological macromolecule is being administered to a patient and is expected to perform its natural biological function, delivery vehicles must be able to release active molecules, at a rate that is consistent with the needs of the particular patient or the disease process.
One specific biological macromolecule, the hormone insulin, contributes to the normal regulation of blood glucose levels through its release by the pancreas, more specifically by the B-cells of a major type of pancreatic tissue (the islets of Langerhans). Insulin secretion is a regulated process which, in normal subjects, provides stable concentrations of glucose in blood during both fasting and feeding. Diabetes is a disease state in which the pancreas does not release insulin at levels capable of controlling glucose levels. Diabetes is classified into two types. The first type is diabetes that is insulin dependent and usually appears in young people. The islet cells of the pancreas stop producing insulin mainly due to autoimmune destruction and the patient must inject himself with the missing hormone. These Type 1 diabetic patients are the minority of total diabetic patients (up to 10% of the entire diabetic population). The second type of diabetes (type 2) is non-insulin dependent diabetes, which is caused by a combination of insulin resistance and insufficient insulin secretion. This is the most common type of diabetes in the Western world. Close to 8% of the adult population of various countries around the world, including the United States, have Type 2 diabetes, and about 30% of these patients will need to use insulin at some point during their life span due to secondary pancreas exhaustion.
Diabetes is the sixth leading cause of death in the United States and accounted for more than 193,000 deaths in 1997. However, this is an underestimate because diabetes contributes to substantially many deaths that are ultimately ascribed to other causes, such as cardiovascular disease. Complications resulting from diabetes are a major cause of morbidity in the population. For example, diabetic retinopathy is the leading cause of blindness in adults aged 20 through 74 years, and diabetic kidney disease accounts for 40% of all new cases of end-stage renal disease. Diabetes is the leading cause for amputation of limbs in the United States. Heart disease and strokes occur two to four times more frequently in adults with diabetes than in adult non-diabetics. Diabetes causes special problems during pregnancy, and the rate of congenital malformations can be five times higher in the children of women with diabetes.
The main cause of mortality with Diabetes Mellitus is long term micro- and macro-vascular disease. Cardiovascular disease is responsible for up to 80% of the deaths of Type II diabetic patients. See, for example, Kirpichnikov et al., Trends Endocrinol Metab 12, 225-30 (2001); Garcia et al., Diabetes 23, 105-11 (1974); Haffner et al., N Engl J Med 339, 229-34 (1998); Sowers, Arch Intert Med 158, 617-21 (1998); Khaw, K. T. et al., Bmj 322, 15-8 (2001). Diabetics have a two- to four-fold increase in the risk of coronary artery disease, equal that of patients who have survived a stroke or myocardial infarction. See, for example, Haffner et al., N Engl J Med 339, 229-34 (1998); Sowers, Arch Intern Med 158, 617-21(1998). This increased risk of coronary artery disease combined with an increase in hypertensive cardiomyopathy manifests itself in an increase in the risk of congestive heart failure. Stratton et al., Bmj 321, 405-12 (2000); Shindler, D. M. et al., Am J Cardiol 77, 1017-20 (1996). These vascular complications lead to neuropathies, retinopathies and peripheral vascular disease. See Kirpichnikov et al., Trends Endocrinol Metab 12, 225-30 (2001). There is a need for diabetes treatments that will decrease the prevalence of such vascular disease in diabetes patients.
The beneficial effects of tight glycemic control on the chronic complications of diabetes are widely accepted in clinical practice. However, only recently it has been firmly established that elevated blood glucose levels are a direct cause of long-term complications of diabetes. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) both showed that control of blood glucose at levels as close to normal as possible prevents and retards development of diabetic retinopathy, nephropathy, neuropathy, and microvascular disease. Drug therapy of diabetes type II has consisted of oral antidiabetic agents and insulin if and when the oral agents fail. Insulin therapy in type I diabetes is essential and is intended to replace the absent endogenous insulin with an exogenous insulin supply. Because insulin is a protein drug (MW approx. 6000 Da) that is not absorbed in the gastrointestinal tract, it ordinarily C requires parenteral administration such as by subcutaneous injection.
The problem of providing bioavailable unmodified human insulin, in a useful form, to the ever increasing population of diabetics has occupied physicians and scientists for almost 100 years. Many attempts have been made to solve some of the problems of stability and biological delivery of this small protein. Most diabetic patients self-administer insulin by daily subcutaneous injections. However, the limitations of multiple daily injections, such as inconvenience, poor patient acceptability, compliance and the difficulty of matching postprandial insulin availability to postprandial requirements, are some of the better known shortcomings of insulin therapy.
Despite studies demonstrating the beneficial effects of tight glycemic control on chronic complications of diabetes, clinicians are not particularly keen on aggressive insulin therapy, particularly in the early stages of the disease, and this is widely accepted in clinical practice. The unmet challenge of achieving tight glycemic control is due, in part, to the shortcomings of the available subcutaneous route of insulin administration and the fear of hypoglycemia. In addition to the practical limitations of multiple daily injections discussed above, the shortcomings of the commonly available subcutaneous route of insulin administration have resulted in the generally inadequate glycemic control associated with many of the chronic complications associated with diabetes. Elevated systemic levels of insulin lead to increased glucose uptake, glycogen synthesis, glycolysis, fatty acid synthesis and triacylglycerol synthesis, leading to the expression of key genes that result in greater utilization of glucose.
In the field of insulin delivery, where multiple repeated administrations are required on a daily basis throughout the patient's life, it would be desirable to create compositions of insulin that maintain protein tertiary structure so as not to alter physiological clinical activity and stability and do not require injections. It would also be desirable to provide compositions of insulin that could be orally administrable, e.g., absorbed from the gastrointestinal tract in adequate concentrations, such that insulin is bioavailable and bioactive after oral administration. Oral absorption allows delivery directly to the portal circulation.
A method of providing insulin without the need for injections has been a goal in drug delivery. Insulin absorption in the gastrointestinal tract is prevented by its large size and enzymatic degradation. It would be desirable to create an oral pharmaceutical formulation of a drug such as insulin (which is not normally orally administrable due to, e.g., insufficient absorption from the gastrointestintal tract), which formulation would provide sufficient absorption and pharmacokinetic/pharmacodynamic properties to provide the desired therapeutic effect.
Insulin exemplifies the problems confronted in the art in designing an effective oral drug delivery system for biological macromolecules. The medicinal properties of insulin can be readily altered using any number of techniques, but its physicochemical properties and susceptibility to enzymatic digestion have precluded the design of a commercially viable oral or alternate delivery system.
Accordingly, there is a need for a method of administering insulin to patients in need of insulin wherein those patients are not subject to systemic hyperinsulinema, which by itself can increase the risk of vascular disease (that is normally associated with such chronic insulin treatments, as discussed above). In other words, it is desirable to provide compositions and methods for treating diabetes without the drawbacks of systemic hyperglycemia to decrease the incidence of vascular complications and other detrimental effects.